DE68918991T2 - Use of vanillin derivatives in the manufacture of a medicament for the treatment of herpes simplex infection. - Google Patents

Abstract

The present invention provides methods of treating or preventing herpes simplex infections in humans and lower animals by treatment with natural and synthetic vanilloid compounds, and the pharmaceutically-acceptable salts and amides thereof, having the general structure: <CHEM> n = 0 or 1; the -W-X- moiety is selected from -C(O)NH-, -C(S)NH-, -S(0)2NH-, -NHC(O)O-, -NHC(S)O-, -NHC(O)NH-, -NHC(S)NH-, -C(O)O-, -C(O)S- and -C(O)N(R)-, wherein either available bond of the -W-X-moiety may be bonded to the -R moiety, with the other bond being attached to the benzyl carbon atom, or directly attached to the benzene ring; the -R<1> moiety is selected from hydrogen, hydroxy, alkyl esters of hydroxy having from about 1 to about 5 carbon atoms, alkyl having from about 1 to about 5 carbon atoms, and alkoxy having from about 1 to about 5 carbon atoms; the -Z moiety is selected from hydrogen, hydroxy and methoxy; the -Y- moiety is selected from -O-, -S-, -NH-, -OC(O)-, -OSO3=- and -OPO3=-; the -V moiety is selected from hydrogen, short chain alkyl, and -CR<2>2-CR<2>2-NH2; the -R<2> moieties are each independently selected from hydrogen, halogen, unsubstituted or substituted alkyl having from about 1 to about 6 carbon atoms, substituted or unsubstituted aryl, and carboxylate, or two -R<2> moieties are covalently bonded to form a substituted or unsubstituted alkyl or heteroalkyl ring having from about 3 to about 8 atoms in the ring including from 0 to about 3 heteroatoms; and the -R moiety is a C2-C24 alkyl moiety which may be straight, branched or cyclic chain and may be saturated, monounsaturated, or polyunsaturated, substituted or unsubstituted, or two -R moieties are covalently bonded to form a substituted or unsubstituted alkyl ring having from about 2 to about 14 carbon atoms in the ring.

Description

This application relates to the use of vanillin-like compounds for the treatment or prevention of herpes simplex infections.

The present invention relates to a new use of natural and synthetic vanillin-like compounds. The following are non-limiting examples of such vanillin-like compounds and references in which they are described. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) and "synthetic" capsaicin (N-vanillylnonanamide) in U.S. Patent 4,313,958, LaHann, issued February 2, 1982; Capsaicin, in Yaksh et al., Science, 206, pp. 481-483 (1979); Capsaicin, in Jancso et al., Naunyn-Schmiedeberg's Arch.Pharmacol., vol. 311, pp. 285-288 (1980); Capsaicin, in Holzer et al., Eur.J.Pharm., Vol. 58, pp. 511-514 (1979); 3-hydroxy-acetanilide, in U.S. Patent 4,238,508, Nelson, issued December 9, 1980; hydroxyphenylacetamides, in EP-A-0089710, LaHann et al., published September 28, 1983; N-vanillylsulfonamides, in U.S. Patent 4,401,663, Buckwalter et al., issued August 30, 1983; hydroxyphenylacetamides, in U.S. Patent 4,424,205, LaHann et al., issued January 31, 1984; N-(3- or 4-hydroxy- or 3,4-dihydroxybenzyl)-carbamates, in U.S. Patent 4,443,473, Buckwalter et al., issued April 17, 1984; N-[(substituted phenyl)-methyl]-cis-monounsaturated alkeneamides, in U.S. Patent 4,493,848, LaHann et al., issued January 15, 1985; N-(3-methoxy-4-hydroxybenzyl- and phenyl)-ureas and thioureas, in U.S. Patent 4,460,602, Buckwalter et al., issued July 17, 1984; N-vanillylureas, in EP-A-0068590, Buckwalter et al., published January 5, 1983; N-[(substituted phenyl)methyl]-alkynamides, in U.S. Patent 4,532,139, Janusz et al., issued July 30, 1985; methylene-substituted N-[(substituted phenyl)methyl]-alkanamides, in U.S. Patent 4,544,668, Janusz et al., issued October 1, 1985; N-[(substituted phenyl)methyl]-diunsaturated amides, in U.S. Patent 4,544,669, LaHann et al., issued October 1, 1985; monoalkenamides, in U.S. Patent 4,564,633, LaHann et al., issued January 14, 1986; substituted phenylacetic acid esters, in UK Patent No. 2,168,974, Loomans et al., published July 2, 1986; N-(substituted alkyl)alkanamides and thioamides, UK Patent No. 2,168,976, Loomans et al., published July 2, 1986; substituted aromatic aralkanamides, UK Patent No. 2,168,975, Janusz et al., published July 2, 1986; and beta-aminoethyl substituted phenyl compounds, EPO No. 282,127, Gardner et al., published September 14, 1988.

The above references generally indicate that the vanillin-like compounds have analgesic, anti-irritant and anti-inflammatory effects.

The use of capsaicin to influence the nervous system of humans and other animals, and to treat the pain associated with herpes zoster ("shingles") infections, has been described in a number of references. Handwerker, HO, U. Holzer-Petsche, Ch. Heym and E. Welk, in "C-Fibre Functions After Topical Application of Capsaicin to a Peripheral Nerve and after Neonatal Capsaicin Treatment", Antidromic Vasodilation and Neurogenic Inflammation: Satellite Symposium of the 29th International Congress of Physiological Sciences, Newcastle, Australia, 1983 ed. Chahl, LA, J. Szolcsanyi and F. Lembeck, Akademiai Kiado, Budapest (1984), pp. 57-78, state that after repeated capsaicin application the nociceptors become desensitized to subsequent chemical stimuli and presumably also to thermal stimuli. Taylor, DCM, Fr.-K. Pierau and J. Szolcsanyi, in "The Effect of Capsaicin on Axoplasmic Transport in a Rat Peripheral Nerve", Antidromic Vasodilation and Neurogenic Inflammation: Satellite Symposium of the 29th International Congress of Physiological Sciences, Newcastle, Australian, 1983, eds. Chahl, LA, Szolcsanyi, J. and F. Lembeck, Akademiai Kiado, Budapest (1984), pp. 165-171, state that systemic capsaicin reduced the amounts of substance P in the dorsal root ganglia (the spindle-shaped swellings of the posterior spinal roots) and in the spinal cord, and that the transport of nerve growth factor (NGF) in the peripheral nerves can be blocked by systemic capsaicin. Jancso, G., F. Obal, Jr., I. Toth-Kasa, M. Katona and S. Husz, in "The Modulation of Cutaneous Inflammatory Reactions by Peptide- Containing Sensory Nerves", International Journal of Tissue Reactions, Vol. VII (1985), pp. 449-457, describe a possible role that the nervous system plays in the inflammatory mechanisms by peptide-containing sensory nerves. While rats treated neonatally with capsaicin showed a complete abrogation of neurogenic inflammation, repeated topical application of capsaicin to the skin (local desensitization) abrogated the neurogenic inflammatory response for several days, and this abrogation was accompanied by a greatly reduced sensitivity to chemically induced pain and increased pain thresholds to warm and hot. Local desensitization of the skin with capsaicin prevented callus formation, rash and itching in patients suffering from acquired urticaria to cold and hot. Jancso, G., S. Husz and N. Simon, in "Impairment of Axon Reflex Vasodilatation after Herpes Zoster", Clinical and Experimental Dermatology, Vol. 8 (1983), pp. 27-31, describe an effect on chemosensitive primary sensory neurons and an impairment of axon reflex-induced vasodilatation of skin vessels after herpes zoster infection and the possible mechanisms by which the vascular responses of the skin may be impaired by herpes zoster.

Capsaicin has been described as an effective compound for treating the severe pain associated with herpes zoster infections. Bernstein, JE, in "Capsaicin in the Treatment of Dermatologic Disease," Cutis, Vol. 39 (April 1987), pp. 352-353, describes the use of capsaicin in the possible treatment of post-herpetic neuralgia and psoriasis. Bernstein, JE, DR Bickers, MV Dahl, Jay Y. Roshal, in "Treatment of Chronic Postherpetic Neuralgia with Topical Capsaicin," Journal of the American Academy of Dermatology, Vol. 17 (1981), pp. 93-96, describe the topical application of capsaicin to patients suffering from post-herpetic neuralgia as a possible method for alleviating post-herpetic neuralgia and other syndromes which characterized by severe, localized pain. U.S. Patent No. 4,536,404, issued August 20, 1985 to Bernstein, describes a method for treating post-herpetic neuralgia due to herpes zoster, which comprises applying an effective amount of capsaicin topically to the herpes zoster affected area to relieve the symptoms of post-herpetic neuralgia.

The effect of capsaicin on the neurogenic response in the skin and on sensory transmission in mice with herpes simplex infections is described in the following two references. Harbour, D.A., T.J. Hill, and W.A. Blyth, in "Recurrent Herpes Simplex in the Mouse: Inflammation in the Skin and Activation of Virus in the Ganglia Following Peripheral Stimulation," Journal of General Virology, vol. 64 (1983), pp. 1491-1498, describe chemical stimuli to the skin that induce recurrent herpes simplex virus disease and reactivation of infectious virus in the ganglia. Mice are injected subcutaneously with capsaicin before being injected with the same dye to help determine the effect of mediators on blood vessel permeability. Ljungdahl, A., K. Kristensson, J.M. Lundberg, E. Lycke, B. Svennerholm and R. Ziegler, in "Herpes Simplex Virus Infection in Capsaicin-Treated Mice", Journal of the Neurological Sciences, vol. 72 (1986), pp. 223-230, state that subcutaneous injection of capsaicin prior to inoculation of the snouts of four-day-old (neonatal) mice with herpes simplex virus (HSV) reduced the mortality rate of HSV-infected mice.

Herpes zoster infections

Herpes zoster infections are caused by the varicella zoster virus (VZV), the causative agent of the conditions commonly referred to as shingles, zona, and acute posterior ganglionitis.

VZV infections usually cause severe pain and result in large clusters of lesions distributed along the course of a sensory nerve. Vesicular eruptions cause neuralgic pain in the area of skin supplied by the peripheral sensory nerves. Vesicular eruptions of herpes zoster are often activated by local lesions involving the dorsal root ganglia (the spindle-shaped swellings of the posterior spinal roots), systemic diseases such as Hodgkin's disease (= lymphogranulomatosis) and immunosuppressive therapy.

VZV is also the causative agent of chickenpox. Subsequent herpes zoster infections (or outbreaks of shingles) are most common after the age of 50. Large numbers of vesicles form on an erythematous base and follow the sensory distribution of one or more dorsal root ganglia (the spindle-shaped swellings of the posterior roots of the spinal cord). The affected sensory zone on the skin is usually hyperaesthetic (= hypersensitive) and accompanied by severe pain.

Post-herpetic neuralgia (= nerve pain) often occurs in patients over 60 years of age following a vesicular eruption caused by VZV. The eruption is usually followed by a syndrome of rash and pain. The rash generally resolves spontaneously after 2 to 3 weeks. However, the pain may persist and be severe. Treatment of post-herpetic neuralgia has often been unsatisfactory and is essentially symptomatic, often requiring strong analgesics and tranquilizers. Post-herpetic neuralgia associated with VZV infections may persist for months or years. The pain may be so persistent that it has been associated with long-term depression and even suicide. It is not uncommon for the pain to be so severe and persistent that neurosurgical procedures may be used in an effort to relieve the patient’s symptoms.

Herpes zoster infections rarely recur in a patient (the relapse rate is less than 2%); an attack, which is generally associated with an eruption of lesions in any of numerous areas of the skin surface, usually confers immunity.

Herpes simplex infections

Clinically, herpes zoster infections may have some similarity to herpes simplex virus (HSV) infections, but there are several important differences between these two infections.

Herpes simplex lesions are characterized by generalized or localized skin and mucous membrane lesions, often with associated constitutional (general, non-localized) severe symptoms. Following an acute primary skin infection, the virus spreads along the sensory nerves and establishes itself in the regional sensory ganglia or in the area of neuronal cell bodies. HSV is usually present in conjunction with latent infections in the trigeminal ganglia or in the ganglia of the presacral nerves. Although VZV infections generally result in latent infections, they are mainly found in the spinal ganglia (spindle-shaped swellings of the posterior spinal roots).

HSV infections are generally of two types, namely type I or type II. Type I HSV infections are mainly those that present as herpes infections in the mouth or eye area. Type II HSV infections are usually genital and are transmitted primarily by direct contact with herpes lesions. Although herpes simplex lesions can appear anywhere on the skin or mucous membranes, they most commonly occur on the mouth, lips, conjunctiva and cornea, and genitals.

In contrast to the 2% relapse rate for VZV infections, the probability of recurrence for HSV type I is 80%, while the probability of recurrence for HSV type II is 50%. Reinfection with various strains of HSV type II can also occur. Recurrent herpetic eruptions can be triggered by circumstances as wide-ranging as excessive exposure to sunlight, feverish illness, physical or emotional stress, or by certain foods or drugs.

Post-herpetic neuralgia does not generally occur in HSV infections. The primary lesions of HSV infection (the vesicular eruptions) are the most painful, the longest lasting, and the most widespread. During periods of vesicular eruption, patients often experience pain in the area of viral infection. And although this pain may be severe, it resolves as the herpetic lesions heal, and the patient remains essentially asymptomatic between recurrent herpetic episodes, unlike VZV infections. Treatment regimens for recurrent HSV infections have shown little promise in preventing herpetic lesions, although there has been some relief of pain and other symptoms.

Objectives of the present invention

An object of the present invention is to provide new methods which are effective for treating or preventing herpes simplex infections of type I and type II and the associated recurrent complaints, lesions and pain.

Another object of the present invention is to provide a medicament for topical treatments for resolving many of the symptoms associated with herpes simplex infections; particularly those associated with herpes type II infections.

Yet another object of the present invention is to provide a topically administered medicament which produces analgesia without loss of mechanical sensation (i.e., "numbing") or without loss of motor coordination.

Yet another object of the present invention is to provide methods for treating or preventing genital herpes simplex infections and the associated recurrent discomfort, lesions and pain (particularly herpes simplex type II infections).

SUMMARY OF THE INVENTION

The present invention comprises the use of natural and synthetic vanillin-like compounds and pharmaceutically acceptable salts thereof for the preparation of medicines for the treatment or prevention of herpes simplex infections in humans or lower animals.

This invention particularly relates to the use of natural and synthetic vanillin-like compounds and pharmaceutically acceptable salts thereof for the preparation of medications which are applied topically to prevent the recurrence of herpes simplex type I or type II lesions.

DETAILED DESCRIPTION OF THE INVENTION

The term "alkyl" as used herein refers to carbon-containing chains which may be straight, branched or cyclic; substituted or unsubstituted; and which may be saturated, monounsaturated (namely may have a double or triple bond in the chain), or polyunsaturated (namely, e.g. may have two or more double bonds in the chain; two or more triple bonds in the chain; or may have one or more double bonds and one or more triple bonds in the chain). Unless otherwise stated, the alkyl groups are preferably of the type listed below. Preferred alkyl groups are straight-chain or branched-chain, in particular straight-chain. Preferred alkyl groups are unsubstituted. Preferred alkyl groups are monounsaturated, in particular saturated. Preferred alkyl groups are C₁-C₂₀-, more preferably C₁-C₁₀-, even more preferably C₁-C₆-, even more preferably C₁-C₄-, and most preferably C₁-C₂-groups, especially C₁-groups.

The term "carboxylate" as used herein means the residue of an organic carboxylic acid (namely -CO₂H), and the salts (e.g. the sodium; potassium; calcium; triethylammonium salts), esters (e.g. methyl ester; ethyl ester) and amides (e.g. unsubstituted amide; N-methylamide; N,N-dimethylamide) thereof which are acceptable from the standpoint of toxicity for administration to humans or lower animals.

The term "aryl" as used herein refers to aryl rings which may be mono-, di- or tri-substituted or unsubstituted (in particular substituted or unsubstituted phenyl or naphthyl). More preferably, the aryl for phenyl. The aryl is more preferably unsubstituted.

The term "substituted" as used herein in connection with alkyl and aryl groups means alkyl or aryl groups which may be mono- or poly-substituted. Preferably they are mono-, di- or tri-substituted; and more preferably mono-substituted. Preferred substituents are selected from a group consisting of halogen, hydroxy, amino, thiol, aryl, alkyl, carboxylate and OR, wherein R is an aryl group or an unsubstituted alkyl group (especially a methoxy or ethoxy group).

For the purposes of the present specification, saturated alkyl groups are referred to as "alkanyl"; unsaturated alkyl groups containing double bonds in the chain are referred to as "alkenyl" (with preference being given to those chains in which the double bonds are in the geometric "Z" or "cis" configuration); and unsaturated alkyl groups containing triple bonds in the chain are referred to as "alkynyl". To designate geometric configurations for any double bonds present in the compounds of the present invention, the nomenclature "Z" and "E" known in the art is used, which is described in detail in Morrison and Boyd, "Organic Chemistry", 3rd ed. (Allyn and Bacon, Inc., Boston; 1973), pp. 131-133 and 148-151; and in March, "Advanced Organic Chemistry", 2nd ed. (McGraw-Hill Book Company, New York; 1977), pp. 86-124; the disclosures of both of these references are incorporated in their entirety by reference.

The compounds useful in the present invention are natural and synthetic vanillin-like compounds and the pharmaceutically acceptable salts thereof, which compounds have the general structure:

exhibit.

In the structure (1) n stands for 0 or 1.

In structure (1), the -W-X- radical is selected from -C(O)NH-, -C(S)NH-, -S(O)2NH-, -NHC(O)O-, -NHC(S)O-, -NHC(O)NH-, -NHC(S)NH-, -C(O)O-, -C(O)S- and -C(O)N(R)-. A preferred -W-X- radical is selected from -C(O)NH-, -C(S)NH-, -NHC(O)NH-, -NHC(S)NH- and -S(O)2NH-. More preferably -W-X- is selected from -C(O)NH-, -C(S)NH- and -NHC(O)NH-. The most preferred -W-X- is -C(O)NH-. Either one or the other available bond of the residue -W-X- can be bonded to the residue R, with the other bond being directly bonded to the benzyl carbon atom, or being directly bonded to the benzene ring.

In structure (1), the group -R¹ is selected from hydrogen, hydroxy, alkyl esters of hydroxy having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms, and alkoxy having 1 to 5 carbon atoms. A preferred group -R¹ is selected from hydrogen, hydroxy, and methyl; and most preferably -R¹ is hydrogen.

In structure (1), the -Z group is selected from hydrogen, hydroxy and methoxy; a preferred -Z group is selected from hydroxy and methoxy. Most preferably -Z is methoxy.

In structure (1), the group -Y- is selected from -O-, -S-, -NH-, -OC(O)-, OSO₃²⁻- and -OPO₃²⁻-; a preferred group -Y- is selected from -O-, -S- and -NH-. A more preferred group -Y- is selected from -O- and -S-; and the most preferred group -Y- is -O-.

In structure (1) the radical -V is selected from hydrogen, -CR²₂-CR²₂-NH₂ and C₁-C₃-alkyl. An even more preferred radical -V is selected from hydrogen and methyl, especially hydrogen. Also more preferred is -CR²₂-CR²₂-NH₂.

The radicals -R² are each independently selected from hydrogen, halogen, unsubstituted or substituted alkyl having 1 to 5 carbon atoms, substituted or unsubstituted aryl and carboxylate; or two radicals -R² are covalently linked to form a substituted or unsubstituted Alkyl ring having 3 to 7 carbon atoms in the ring. It is preferred that at least one -R² radical on the alpha carbon atom (the carbon atom directly bonded to the Y radical) is hydrogen. It is also preferred that all -R² radicals are selected from hydrogen and hydroxyalkyl having 1 to 5 carbon atoms, and more preferably represent 5-hydroxypentyl, 2-hydroxybutyl or hydroxymethyl, especially hydroxymethyl. It is also preferred that all -R² radicals are selected from hydrogen and aminoalkyl having 1 to 5 carbon atoms, and more preferably represent 2-aminopentyl, 2-aminobutyl, aminomethyl or aminoethyl, especially aminomethyl or aminoethyl. It is also preferred that all -R² radicals are selected from hydrogen and substituted or unsubstituted aryl, especially phenyl or methylphenyl. Preferred -R² radicals which are aryl groups include phenyl, naphthyl and substituted phenyl or naphthyl; and are most preferably substituted or unsubstituted phenyl. Preferred -R² radicals which are arylalkyl groups are substituted, or - preferably - unsubstituted. Preferred -R² radicals which are substituted arylalkyl groups are those in which the substituent groups are independently selected from halogen, hydroxy, amino, hydrogen and carboxyl groups. It is also preferred that all -R² radicals are selected from hydrogen and alkyl of 1 to 5 carbon atoms (and in particular are methyl). It is also preferred that at most only one -R² radical is other than hydrogen. It is also preferred that all -R² radicals are hydrogen.

It is particularly preferred that both -R² radicals on the alpha carbon atom are hydrogen and that both -R² radicals on the beta carbon atom (the carbon atom directly bonded to the alpha carbon atom) are unsubstituted or substituted alkyl or are covalently bonded to form a substituted or unsubstituted alkyl or heteroalkyl ring having 3 to 8 atoms, including 0 to 3 heteroatoms, in the ring. The term "heteroatoms" as used herein means atoms other than carbon which can bond covalently to at least two other atoms and become part of a stable ring structure. Preferred heteroatoms are N, O and S. More preferably, the -R² radicals on the beta carbon atom are unsubstituted or substituted C₁-C₆ alkyl, more preferably C₁-C₄ alkyl, and even more preferably C₁-C₂ alkyl. It is also preferred that the two -R² radicals on the beta carbon atom are covalently bonded to form a substituted or unsubstituted alkyl ring having 3 to 6 carbon atoms in the ring, more preferably having 3 or 4 or 5 carbon atoms in the ring. Preferred alkyl radicals -R² on the beta carbon atom are saturated or unsaturated and they have a single bond, a double bond or a triple bond, it being more preferred that both radicals -R² on the beta carbon atom are unsubstituted or substituted alkanyl or are covalently bonded to form an unsubstituted or substituted alkanyl ring. Preferred substituents of the alkyl radicals -R² on the beta carbon atom are hydroxy, amino, thiol and carboxylate, especially hydroxy and amino. It is more preferred that all alkyl radicals -R² on the beta carbon atom are unsubstituted. It is even more preferred that both radicals -R² on the beta carbon atom are methyl or ethyl, especially methyl.

In structure (1), the -R radical is a C₂-C₂₄ alkyl radical which may have a straight, branched or cyclic chain and which may be saturated, monounsaturated or polyunsaturated, substituted or unsubstituted. Preferred -R radicals are straight or branched chain alkanyl, straight or branched chain monounsaturated alkyl, straight or branched chain diunsaturated alkyl, and straight or branched chain triunsaturated alkyl. More preferably, the -R radicals are mono- or diunsaturated or saturated, straight or branched chain C₆-C₂₄ alkyl groups. Also preferred to a greater extent are straight-chain C₅-C₁₁-alkyl groups, in particular straight-chain C₇-C₁₀-alkanyl groups. Even more preferred are mono- or diunsaturated alkenyl groups, or straight-chain C₆ -C₂₄ -alkenyl groups. Also preferred are monounsaturated, straight-chain C₁₁-C₂₃-alkenyl groups with a cis double bond. Even more preferred are monounsaturated, straight-chain C₁₇-C₂₃-alkenyl groups with a cis double bond. The most preferred radical -R is 9-Z-octadecenyl.

The preferred groups -R are those listed below. For the medicaments to be used according to the present invention which contain phenylacetic acid amide or thioamide derivatives, in particular the beta-aminoethoxy substituted compounds of the general structure:

the preferred -R groups are selected from n-hexanyl, n-heptanyl, n-octanyl, n-nonanyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, docosenyl, octadecadienyl, nonadecadienyl, eicosadienyl, octadecatrienyl, eicosatrienyl, eicosatetraenyl, octadecinyl, nonadecinyl, eicosinyl and docosinyl. More preferred -R groups are selected from n-octanyl; n-nonanyl; n-decanyl; 9E- or 9Z-tetradecenyl; 9E- or 9Z-hexadecenyl; 9E- or 9Z-octadecenyl; 6E- or 6Z-octadecenyl; 11E- or 11Z-octadecenyl; 10E- or 10Z-nonadecenyl; 13E- or 13Z- docosenyl; 9-methylene-1-octadecanyl, 9Z, 12Z-octadecadienyl; 9E, 12E-octadecadienyl; 9Z, 12E-octadecadienyl; 9Z, 11E-octadecadienyl; 10E, 13E-nonadecadienyl; 11E, 14E-Eicosadienyl; 9Z,12Z,15Z-octadecatrienyl; 6Z, 9Z,12Z-octadecatrienyl; IIZ,14Z,17Z-eicosatrienyl; 5Z,8Z,11Z,14Z-eicosatetraenyl; and 9-octadecynyl. Most preferred groups - R are n-octanyl, n-nonanyl and 9Z-octadecenyl.

For the compounds of the present invention which are vanillylamide or vanillylthioamide derivatives and in particular the beta-aminoethoxy substituted compounds having the general structure:

the preferred -R groups are selected from n-hexanyl, n-heptanyl, n-octanyl, n-nonanyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, docosenyl, heptadecadienyl, octadecadienyl, nonadecadienyl, eicosadienyl, heptadecatrienyl, octadecatrienyl, nonadecatrienyl, eicosatrienyl, nonadecatetraenyl, heptadecinyl, octadecinyl, nonadecinyl and eicosinyl. More preferred -R groups are selected from n-heptanyl; n-octanyl; n- Nonanyl; 8E- or 8Z-tridecenyl; 8E- or 8Z-pentadecenyl; 8E- or 8Z-heptadecenyl; 5E- or 5Z-heptadecenyl, 10E- or 10Z- heptadecenyl; 9E- or 9Z-octadecenyl; 12E- or 12z-nonadecenyl; 8-methylene-1-heptadecanyl; 8Z, 11Z-heptadecadienyl; 8E, 11E-heptadecadienyl; 8Z, 11E-heptadecadienyl; 8Z, 10E-heptadecadienyl; 9E, 12E-octadecadienyl; 10E, 13E-nonadecadienyl; 8Z, 11Z, 14Z-heptadecatrienyl; 5Z, 8Z, 11Z-heptadecatrienyl; 10Z, 13Z, 16Z-nonadecatrienyl; 4Z, 7Z,10Z, 13Z-nonadecatetraenyl; and 8-heptadecynyl. The most preferred -R groups are n-heptanyl, n-octanyl and 8Z-heptadecenyl (namely oleoylamide).

The alkyl groups -R can be substituted or - preferably - unsubstituted. The preferred substituents are selected from a group consisting of halogen, hydroxy, amino, aryl, carboxylate and -OR³, where -R³ is an unsubstituted alkyl group having 1 to 3 carbon atoms (especially methoxy and ethoxy). It is preferred that the substituted alkyl groups are mono-, di- or tri-substituted, and most preferably mono-substituted. If -W-X- is -C(O)N(R)-, then the two groups -R can be covalently bonded to form a substituted or unsubstituted alkyl ring having 2 to 14 carbon atoms in the ring.

The term "pharmaceutically acceptable salts and amides" as used herein refers to the compounds in their salt or amide form which have the same general pharmacological properties as the parent amino form from which they are derived and which are acceptable from a toxicity standpoint. Pharmaceutically acceptable salts include ammonium salts derived from inorganic acids (e.g., HCl, HBr, NaHSO4, H2CO3) and carboxylic acid ammonium salts derived from organic carboxylic acids (e.g., acetic; lactic; gluconic; citric; glucuronic; galacturonic; fumaric; gentisic; lactobionic; and benzoic). The pharmaceutically acceptable amides include those derived from organic carboxylic acids (e.g. acetic acid amides), including those derived from amino acids (e.g. glycinamides). Preferred are the carboxylic acid ammonium salts derived from organic carboxylic acids, especially the acetate and lactate salts.

Preferred compounds suitable for use in the medicaments of the present invention include 8-methyl-N-vanillyl-6-nonenamide; N-vanillylnonanamide; N-vanillyl-9-octadecenamide; N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-((4-(2-aminoethoxy)-3- methoxyphenyl)-methyl)-nonanamide; N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-nonanamide; N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-((4-(2-amino-3-methylbutoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-((4-(1-Amino-1-cyclopropylmethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-((4-(1-Amino-1-cyclopentylmethoxy)-3- methoxy) phenyl)methyl)-9Z-octadecenamide; N-(9Z-octadecenyl)-4-(2-amino-2-methylpropoxy)-3-methoxyphenylacetamide; N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide; Octanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide; N-((4-(2-Amino-3-hydroxypropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-((4-(2-amino-2-carboxyethoxy)-3-methoxyphenyl)-methyl)- 9Z-octadecenamide; and the pharmaceutically acceptable salts and amides thereof. More preferred compounds to be used in the medicaments according to the present invention suitable include 8-methyl-N-vanillyl-6-nonenamide; N-vanillylnonanamide; N-vanillyl-9-octadecenoamide; N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide; N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamide; N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-nonanamide; N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-(9Z-octadecenyl)-4-(2-amino-2-methylpropoxy)-3-methoxyphenylacetamide and the pharmaceutically acceptable salts and amides thereof.

As mentioned above, capsaicin and a wide variety of other substituted phenyl compounds are known to have analgesic effects. However, to date, capsaicin-like compounds and other vanillin-like compounds have not been shown to have an effect on herpes simplex infections. Surprisingly, natural and synthetic vanillin-like compounds of the present invention are effective in helping to prevent and/or treat recurrent herpes simplex infections.

Specific pharmaceutical compositions useful in the invention are described in the following U.S. Patents: U.S. Patent No. 4,401,663, Buckwalter et al., issued August 30, 1983; U.S. Patent No. 4,424,205, LaHann et al., issued January 31, 1984; U.S. Patent No. 4,443,473, Buckwalter et al., issued April 12, 1984; U.S. Patent No. 4,493,848, LaHann et al., issued January 15, 1985. Representative pharmaceutical compositions useful in the methods of the present invention are found in the non-limiting Examples set forth below. Such pharmaceutical compositions preferably contain one or more of the vanillin-like compounds and a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable carrier" as used in this document means one or more compatible solid or liquid diluents or encapsulating substances intended for administration to a human or to a lower animal. The term "acceptable" as used in the present document means that the components of a pharmaceutical carrier can be mixed with the vanillin-like compounds and with each other in such a way that no interaction occurs which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under the usual conditions of use. Pharmaceutically acceptable carriers must, of course, be of a sufficiently high degree of purity and of a sufficiently low toxicity to be suitable for administration to the human or lower animal being treated.

The pharmaceutically acceptable carrier employed in the medicaments to be used according to the present invention is employed in a concentration sufficient to provide a practical relationship between size and dosage. The pharmaceutically acceptable carriers may comprise a total of 50% to 99.99%, preferably 90% to 99.9%, and more preferably 95% to 99.5%, by weight of the pharmaceutical compositions of the present invention.

Total individual dosages of the vanillin-like compounds present in the pharmaceutical compositions useful in the present invention are generally from 1 µg to 1 g. Preferred individual dosages are from 10 µg to 100 mg; more preferably from 100 µg to 50 mg; and most preferably from 1 mg to 10 mg.

The selection of a pharmaceutically acceptable carrier to be used in conjunction with the compounds of the present invention is essentially determined by the manner in which the compound is to be administered. Such methods include parenteral (particularly subcutaneous), oral and topical. As used herein, the term "topically administered" means bringing the compounds into contact with the skin, mucous membrane or body cavity. Thus, the mode of administration includes epidermal, intraoral, intranasal, intravaginal, intraanal, intraurethral, intraaural and extraocular administration. The preferred use of the vanillin-like compounds for the production of a A preferred embodiment of the present invention is the topical administration of said compounds. Suitable pharmaceutically acceptable carriers for topical application include those suitable for use in lotions, creams, solutions, gels, bandages and the like.

Suitable carriers for topical administration preferably remain in place on the skin as a continuous film and are not readily washed away by perspiration or immersion in water. Generally, the carrier is either organic in nature or an aqueous emulsion and is capable of containing the vanillin-like compound in dispersed or dissolved form. The carrier may contain pharmaceutically acceptable emollients, skin penetration enhancers, colorants, fragrances, emulsifiers, thickeners and solvents. A more detailed description of such forms follows below.

1. Lotions

The lotions may contain an effective amount (preferably 0.001% to 5%, more preferably 0.1% to 1%) of a vanillin-like compound; 1% to 50%, preferably 3% to 15%, of an emollient; the balance being water, a C₂ or C₃ alcohol, or a mixture of water and the alcohol. Various emollients are known. Examples of such emollients are the following:

a. Hydrocarbon oils and waxes. Examples are mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene and perhydrosqualene.

b. Silicone oils, such as dimethylpolysiloxane, methylphenylpolysiloxane, water-soluble and alcohol-soluble silicone-glycol copolymers.

c. Triglyceride fats and oils, such as those derived from vegetable and/or animal sources and/or from marine animals. Examples include castor, safflower, cottonseed, corn, olive, cod liver, almond, avocado, palm, sesame and soybean oil.

d. Acetoglyceride esters, such as acetylated monoglycerides.

e. Ethoxylated glycerides, such as ethoxylated glyceryl monostearate.

f. Alkyl esters of fatty acids having 10 to 20 carbon atoms. Methyl, isopropyl and butyl esters of fatty acids are useful in the present invention. Examples include hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, isopropyl myristate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate, diisopropyl adipate, diisohexyl adipate, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate, myristyl lactate and cetyl lactate.

g. Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examples include oleyl myristate, oleyl stearate and oleyl oleate.

i.e. fatty acids with 9 to 22 carbon atoms. Suitable examples include pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidonic, behenic and erucic acid.

i. Fatty alcohols containing 10 to 22 carbon atoms. Lauryl, myristyl, cetyl, hexadecyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl, behenyl, erucyl and 2-octyldodecyl alcohol are examples of satisfactory fatty alcohols.

j. Fatty alcohol ethers. Ethoxylated fatty alcohols with 10 to 20 carbon atoms include lauryl, cetyl, stearyl, isostearyl, oleyl and cholesterol alcohol, to which 1 to 50 ethylene oxide groups or 1 to 50 propylene oxide groups or a mixture thereof are bonded.

k. Ether esters, such as the fatty acid esters of ethoxylated fatty alcohols.

i. Lanolin and derivatives thereof. Lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated lanolin, acetylated lanolin alcohols, lanolin alcohols linoleate, lanolin alcohols ricinoleate, acetate of lanolin alcohols ricinoleate, acetate of ethoxylated alcohol esters, hydrogenolysis of lanolin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin and liquid and semi-solid lanolin absorption bases are illustrative of lanolin derived emollients.

m. Polyhydric alcohols and polyether derivatives. Propylene glycol, dipropylene glycol, polypropylene glycol (MW 2000-4000), Polyoxyethylene-polyoxypropylene glycols, polyoxypropylene- Polyoxyethylene glycols, glycerin, ethoxylated glycerin, propoxylated glycerin, sorbitol, ethoxylated sorbitol, Hydroxypropylsorbitol, polyethylene glycol (MW 200-6000), methoxypolyethylene glycols 350, 550, 750, 2000, 5000, poly(ethylene oxide) homopolymers (MW 100,000-5,000,000), polyalkylene glycols and derivatives, Hexylene glycol (2-methyl-2, 4-pentanediol), 1,3-butylene glycol, 1,2,6-hexanetriol, ethohexadiol USP (2-ethyl-1,3-hexanediol), vicinal C₁5-C₁8 glycol and polyoxypropylene derivatives of trimethylolpropane are examples.

n. esters of polyhydric alcohols. Ethylene glycol mono- and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (MW 200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol poly-fatty acid esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid esters, sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters are satisfactory esters of polyhydric alcohols.

o. Wax esters, such as beeswax, spermaceti oil, myristyl myristate, stearyl stearate.

p. Beeswax derivatives, e.g. polyoxyethylene sorbitol beeswax. These are reaction products of beeswax with ethoxylated sorbitol of varying ethylene oxide content, which form a mixture of ether esters.

q. Vegetable waxes, including carnauba wax and candelilla wax.

r. Phospholipids, such as lecithin and derivatives thereof.

see sterols. Cholesterol, cholesterol fatty acid esters are examples of this.

t. Amides, such as fatty acid amides, ethoxylated fatty acid amides, solid fatty acid alkanolamides.

The lotions preferably also contain 1% to 10%, more preferably 2% to 5%, of an emulsifier. Emulsifiers can be non-ionic, anionic or cationic. Examples of satisfactory nonionic emulsifiers include fatty alcohols having 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles of ethylene oxide or propylene oxide, alkylphenols having 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono- and di-fatty acid esters of ethylene oxide, mono- and di-fatty acid esters of ethylene glycol wherein the fatty acid residue contains 10 to 20 carbon atoms, diethylene glycol, polyethylene glycols having a molecular weight of 200 to 6000, propylene glycols having a molecular weight of 200 to 3000, glycerin, sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and hydrophilic wax esters. Suitable anionic emulsifiers include the fatty acid soaps, e.g., the sodium, potassium and triethanolamine soaps, wherein the fatty acid moiety contains from 10 to 20 carbon atoms. Other suitable anionic emulsifiers include the alkali metal, ammonium or substituted ammonium alkyl sulfates, alkylaryl sulfonates and alkyl ethoxyether sulfonates having from 10 to 30 carbon atoms in the alkyl moiety. The alkyl ethoxyether sulfonates contain from 1 to 50 ethylene oxide units. Satisfactory cationic emulsifiers are the quaternary ammonium, morpholinium and pyridinium compounds. Certain of the emollients described in the preceding paragraphs also have emulsifying properties. When a lotion is formulated containing such an emollient, no additional emulsifier is required, although one may be incorporated into the composition.

The remainder of the lotion is water or a C2 or C3 alcohol, or a mixture of water and the alcohol. The lotions are formulated simply by mixing all the components together. Preferably, the compound of the present invention is dissolved in the mixture. Conventional optional components may be added. One such additive is a thickener in an amount of from 1% to 10% of the composition. Examples of suitable thickeners include: cross-linked carboxypolymethylene polymers, ethyl cellulose, polyethylene glycols, gum tragacanth, gum karaya, Xanthan gums and bentonite, hydroxyethyl cellulose and hydroxypropyl cellulose.

2. Creams

The creams contain an effective amount (preferably 0.001% to 5%, more preferably 0.1% to 1%) of a vanillin-like compound; and 5% to 50%, preferably 10% to 25%, of an emollient; the balance being water. The emollients described above may also be used in the cream compositions. Optionally, the cream form contains a suitable emulsifier, such as those described above. If an emulsifier is included, it is present in the composition in an amount of from 3% to 50%, preferably from 5% to 20%.

3. Solutions

The solution form contains an effective amount (preferably 0.001% to 5%, more preferably 0.1% to 1%) of a vanillin-like compound; the balance being water and/or a suitable organic solvent. Suitable organic materials useful as a solvent or as part of a solvent system are the following: propylene glycol, polyethylene glycol (MW 200-600), polypropylene glycol (MW 425-2025), glycerin, sorbitol esters, 1,2,6- hexanetriol, ethanol, isopropanol, diethyl tartrate, butanediol and mixtures thereof. Such solvent systems may also contain water.

These compositions in the form of a solution can be applied to the skin as is, or they can be formulated into an aerosol and applied to the skin by spraying. The aerosol compositions further contain from 25% to 80%, preferably from 30% to 50%, of a suitable propellant. Examples of such propellants are the lower molecular weight chlorinated, fluorinated and chlorofluorinated hydrocarbons. Nitrous oxide, carbon dioxide, butane and propane are also used as propellants. These propellants are used in an amount sufficient to expel the contents from the container.

4. Gels

Gel compositions can be formulated simply by adding a suitable thickening agent to the solution compositions described above. Examples of suitable thickening agents have been described above with reference to the lotions.

The gelled compositions contain an effective amount (preferably 0.001% to 5%, more preferably 0.1% to 1%) of a vanillin-like compound; 5% to 75%, preferably 10% to 50%, of an organic solvent as described above; 0.5% to 20%, preferably 1% to 10%, of the thickening agent; the balance being water.

5. Solids

Solid form compositions find use as stick-like compositions intended to be applied to the lips or other parts of the body. Such compositions contain an effective amount (preferably 0.001% to 5%, more preferably 0.1% to 1%) of a vanillin-like compound, and 50% to 98%, preferably 60% to 90%, of the emollients described above. This composition may further contain 1% to 20%, preferably 5% to 15%, of a suitable thickening agent, and optionally emulsifiers and water. The thickening agents described above with reference to the lotions are also suitable here.

6. Genital formulations

The compositions used in the present invention can be administered, particularly in the genital area, in a wide variety of excipients. In addition to general skin treatment, the genital infections can be treated using vaginal, anal or urethral suppositories; vaginal pessaries; vaginal or rectal tablets or pieces for insertion; menstrual and non-menstrual tampons; ointments; enemas; cones; emulsions; and douches.

Additives commonly found in topical compositions, such as preservatives, e.g. methyl and ethyl paraben, dyes and perfumes, may be any of the above be added to the topical compositions described.

The present invention encompasses the use of the medicaments according to the present invention for treating herpes simplex infections, for alleviating the signs and symptoms associated with herpetic vesicular eruptions, and for alleviating the pain associated with herpes simplex lesions. The use of the medicaments according to the present invention may be particularly directed to preventing recurrent herpes simplex infections and/or alleviating the symptoms associated with herpes simplex vesicular eruptions.

The term "safe and effective amount" as used in this material means - within the scope of reasonable medical judgment - an amount of a compound or composition which is large enough to significantly and beneficially modify the condition being treated, but which is sufficiently small to avoid serious side effects (at a reasonable benefit/risk ratio). The safe and effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of any concurrent therapy, the specific compound or composition being used, the particular pharmaceutically acceptable carrier being used, and other factors within the skill and experience of the treating physician. However, daily doses may range from 0.01 mg/kg body weight to 5 mg/kg body weight. Preferred daily doses range from 0.1 mg to 2 mg/kg body weight. Up to 6 individual doses per day may be administered.

Topical administration may be performed by directly applying or spreading a safe and effective amount of a vanillin-like composition onto epidermal or epithelial tissues, including the external skin and oral, anal, vaginal, gingival and nasal tissues. The amount of pharmaceutical composition to be administered topically may vary from 1 mg/cm² to 20 mg/cm²; and when a patch is worn over the affected area, amounts may be higher, depending on such factors as sensitivity, the nature and location of the tissue to be treated, the composition and carrier to be administered, and the particular compound to be administered.

An animal model which can be used to demonstrate the use of vanillin-like compounds to prevent or treat herpes simplex infections is described in Stanberry, L.R., R.L. Burke and M.G. Myers, "Herpes Simplex Virus Glycoprotein Treatment of Recurrent Genital Herpes," The Journal of Infectious Diseases, vol. 157 (1988), pp. 156-163; and in Stanberry, L.R., S. Kit and M.G. Myers, "Thymidine Kinasedeficient Herpes Simplex Virus Type 2 Genital Infection in Guinea Pigs," Journal of Virology, vol. 55 (1985), pp. 322-328.

Example I

Female Hartley guinea pigs (300-350 g) are randomly divided into groups of 12 animals each. A mixture of Tween, EtOH and 0.9% NaCl in distilled water is prepared to give the following concentrations (vol/vol):

10% Tween80

10% EtOH (ethanol)

80% 0.9% NaCl in distilled H₂O

The ethanol/Tween/saline (ETS) vehicle is mixed with capsaicin to obtain a concentration of capsaicin of 1.0%. The capsaicin is administered intravaginally in a 100 μl volume of the (ETS) vehicle.

After administration of capsaicin, guinea pigs are inoculated intravaginally with 5.0 log pfu HSV-II, MS strain. The virological course of the primary infection 1 to 10 days after inoculation is assessed by determining the titer of the virus in secretions collected by daily vaginal swabs. The clinical course of the primary infection is assessed along with the occurrence and duration of urinary retention, hind limb paralysis, and the occurrence of death within 14 days of viral inoculation. The frequency and severity of recurrent disease are determined by examining the guinea pig daily after recovery from the primary infection from days 15 to 21 through day 100 inclusive. The capsaicin-treated animals show no or very few lesions, while the untreated animals show numerous lesions. Similar results are obtained using a 1.0% concentration of the N-vanillylnonamide in the ETS vehicle.

Similar results are also obtained using a 1.0% concentration of N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide in a vehicle consisting of 10% EtOH, 10% Tween 80 and 80% of an aqueous buffer solution consisting of acetic acid (6 g/L) and sodium hydroxide (2 g/L) in distilled water.

Example II

Synthesis of N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide by the phthalimide synthesis method (a) Synthesis of N-((4-(2-bromoethoxy)-3-methoxyphenyl)methyl)- 9Z-octadecenamide:

N-Vanillyl oleamide (100 g, 0.24 mol; prepared as described in U.S. Patent 4,493,848, issued January 15, 1985 to LaHann and Buckwalter), 1,2-dibromoethane (500 mL), 40% KOH (165 mL), and 40% tetrabutylammonium hydroxide (15 mL) are combined in a 2-liter flask equipped with a thermometer, mechanical stirrer, and reflux condenser, and the solution is heated to 55°C. The disappearance of starting material is monitored by TLC. (thin layer chromatography) (6% acetone/CH2C12). After completion of the reaction (typically after allowing the reaction to proceed overnight), the solution is diluted with CHCl3 (500 mL), washed three times with water, and the aqueous washings are then combined and extracted once with CHCl3 (250 mL). The organic phases are combined, washed with 10% H3PO4 (250 mL), saturated NaHCO3 solution (250 mL), and brine, and then they are dried (MgSO4) and filtered. The volume is reduced to less than 500 mL by vacuum distillation, and the liquid is then transferred to a 4 L flask. After cooling to about 10 °C, Et2O (2 L) is added. and the flask is cooled in an ice bath. A white precipitate forms and additional Et2O is added to adjust to a volume of 4 liters. The thick, amorphous solid is filtered, washed with Et2O, dried, and used without further purification.

Mp = 96-97ºC. 1H NMR (CDCl₃) (ppm): 6.8 (s, 3H), 5.9 (m, 1H), 5.3 (t, 2H, J=5Hz), 4.3 (m, 4H), 3.8 (s, 3H), 3.6 (t, 2H, J=6.5 Hz), 2.3-2.1 (m, 4H), 2.0-1.5 (m, 2H) , 1.2 (s, 22H), 0.85 (t, 3H). ¹³C NMR (CDCl₃) (ppm) : 14.0, 22.5, 25.6, 27.0, 29.1, 31.7, 36.5, 43.0, 55.8, 69.3, 111.9, 115.0, 119.8, 129.5, 132.8, 146.5, 149.8, 172.8.

(b) Synthesis of N-((4-(2-phthalimidoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide:

N-((4-(2-bromoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide (615.5 g, 1.17 mol) and DMF are combined in a 5-liter flask equipped with a mechanical stirrer and a thermometer. The mixture is stirred and heated to 55ºC. When the solution has become homogeneous, potassium phthalimide (270.0 g, 1.47 mol) is added and the solution is maintained at 55ºC with good stirring. After about 10 min, the reaction solution has become homogeneous. A white solid then begins to precipitate and the reaction mixture is stirred overnight at 55ºC. TLC (acetone/dichloromethane, 6:94) indicates when the starting material has been consumed. The reaction solution is divided into three equal volumes and each volume is worked up as follows: The solution is poured into a 4-liter beaker and then diluted with water to the 3500 mL mark. After standing for about 15 min, the solution is again divided into two equal parts, each of which is diluted with water to 3500 mL. The white precipitate is removed by filtration and washed several times with water. The three parts are combined and dried in a vacuum oven at 90 ° C for 12 h to give 682.25 g (98%) of a fine powder. M.p. 109.5-111.0 ° C. 1H NMR (CDCl 3 ) (ppm) : 7.8 (m, 4H), 6.8 (m, 3H), 5.8 (m, 1H), 5.3 (t, 2H), 4.3 (d, 2H), 4.2 (t, 2H), 4.1 (t, 2H), 3.7 (s, 3H), 2.2-2.0 (m, 4H), 1.6 (m, 2H), 1.2 (s, 22H), 0.9 (t, 3H). 13C NMR (CDCl3) (ppm) : 172.8, 167.9, 150.0, 147.1, 133.9, 132.5, 132.1, 129.7, 123.1, 120.0, 114.9, 112.0, 66.2, 55.7, 43.2, 37.1, 36.7, 31.8, 29.3, 27.1, 25.7, 22.6, 14.0. IR (CM⊃min;¹) : 3300, 1775, 1715, 1635, 1265, 1230, 1145, 1035, 1025, 720. CI-DEP mass spectrum (m/z) : 591 (MH+).

(c) Synthesis of N-((4-(2-aminoethoxy)-3-methoxyphenyl)-niethyl)-9Z-octadecenamide:

N-((4-(2-phthalimidoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide (250 g, 0.424 mol) and ethanol (2500 ml) are in a 4-liter beaker. The slurry is mechanically stirred and heated to 60ºC. At about 45ºC the solution becomes homogeneous. 1-Hexene (20 mL) is added. Hydrazine hydrate (106 mL of a 64% aqueous solution) is then added. After about 5 min, a white precipitate begins to form. During the 2-hour reaction time, 500 mL of ethanol is added to the reaction mixture to replenish the volume lost by evaporation. The reaction solution is then divided into three equal parts and each part is worked up as follows: Methyl t-butyl ether (1.5 L) is used to transfer the slurry to a 4-liter separatory funnel. Water (1 liter) and 1N NaOH (500 mL) are added and the solution is shaken thoroughly. 50% NaOH (25 mL) is added and the solution is shaken again. The organic phase is then extracted twice with alkali using the same sequence and the extract is washed with brine. The extract is dried over sodium sulfate and concentrated. The crude product is taken up in hot methyl t-butyl ether and allowed to crystallize. The crystals are filtered and dried in a vacuum desiccator to give 124.87 g. A second crop of crystals, 40.82 g, is obtained, giving an overall yield of 85%. M.p. = 102-106 °C. 1H NMR (CDCl3) (ppm) : 6.7 (s, 3H), 6.1 (m, 1H), 5.3 (t, 2H), 4.3 (d, 2H), 3.9 (t, 3H), 3.8 (s, 3H), 3.0 (t, 2H), 2.5 (s, 2H), 2.1-1.6 (m, 4H), 1.5-1.2 (m, 2H), 1.2 (s, 22H), 0.9 (t, 3H). 13C NMR (CDCl₃) (ppm) : 172.9, 149.3, 147.2, 131.8, 129.6, 119.7, 113.5, 111.4, 70.9, 55.5, 42.9, 40.9, 36.4, 31.6, 29.0, 26.9, 25.6, 22.4, 13.8. IR max (cm⁻¹) : 3380, 3300, 1630, 1375, 1255, 1235, 1020, 800, 720 cm⁻¹. CI-DEP mass spectrum 461 (MH+).

Claims (10)

1. Use of a compound for the manufacture of a medicament for the treatment or prevention of vesicular eruptions (lesions) resulting from herpes simplex infections in humans or a lower animal, characterized in that the compound has the general structure: wherein: a) n stands for 0 or 1, preferably 1; b) -W-X- is selected from -C(O)NH-, -C(S)NH-, -S(O)2NH-, -NHC(O)O-, -NHC(S)O-, -NHC(O)NH-, -NHC(S)NH-, -C(O)O-, -C(O)S- and -C(O)N(R)-; preferably from -C(O)NH-, -C(S)NH-, -NHC(O)NH-, -NHC(S)NH- and -S(O)2NH-; more preferably from -C(O)NH- and -C(S)NH-; wherein one available bond of -W-X- is bonded to -R and the other bond is bonded to the benzylic carbon atom or to the benzene ring; c) -R¹ is selected from hydrogen, hydroxy, alkyl esters of hydroxy having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms and alkoxy having 1 to 5 carbon atoms; preferably from -H, -OH and -CH₃; more preferably -H ; d) -Z is selected from -H, -OH and -OCH₃; preferably from -OH and -OCH₃; more preferably -OCH₃; e) -Y- is selected from -O-, -S-, -NH-, -OC(O)-, OSO₃²⁻- and -OPO₃²⁻- preferably from -O-, -S- and -NH-; more preferably is -O-; f) -V is selected from -H, alkyl having 1 to 3 carbon atoms and -CR²₂-CR²₂-NH₂; g) the radicals -R² are independently selected from hydrogen, halogen, unsubstituted or substituted alkyl having 1 to 6 carbon atoms, substituted or unsubstituted aryl and carboxylate, or two radicals -R² are covalently bonded to form a substituted or unsubstituted alkyl- or heteroalkyl ring having 3 to 8 atoms in the ring, including 0 to 3 heteroatoms; and h) -R is selected from C₂-C₂₄-alkyl which is straight, branched or cyclic; saturated, monounsaturated or polyunsaturated; and substituted or unsubstituted; or two radicals -R are covalently bonded to form a substituted or unsubstituted alkyl ring having 2 to 14 carbon atoms in the ring; where -R is preferably selected from unsubstituted, saturated or mono- or di-unsaturated, straight-chain or branched-chain C₆-C₂₄-alkyl ; or the pharmaceutically acceptable salts and amides thereof. 2. Use according to claim 1, characterized in that all -R² radicals on the alpha carbon atom are -H; both -R² radicals on the beta carbon atom are selected from -H, unsubstituted or substituted C₁-C₆ alkyl or the -R² radicals are covalently bonded to form a substituted or unsubstituted C₃-C₆ ring, whereby preferably both -R² radicals on the beta carbon atom are selected from methyl and ethyl or are bonded to form cyclopropyl, cyclobutyl or cyclopentyl. more preferably both radicals are methyl; and -R is saturated or mono- or di-unsaturated by double bonds, straight or branched chain C₁-C₂₄ alkyl; preferably monounsaturated, straight-chain C₁₁-C₂₃-alkenyl with a cis double bond or straight-chain C₇-C₁₀-alkanyl. 3. Use according to claim 2, characterized in that -V is selected from -H and -CH₃. 4. Use according to claim 3, characterized in that this compound is trans-8-methyl-N-vanillyl-6-nonenamide or N- vanillylnonanamide. 5. Use according to claim 2, characterized in that -V stands for -CR²₂-CR²₂-NH₂. 6. Use according to claim 5, characterized in that the compound has the general structure: wherein -R is selected from n-hexanyl, n-heptanyl, n-octanyl, n- nonanyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n- tetradecanyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, docosenyl, octadecadienyl, nonadecadienyl, eicosadienyl, octadecatrienyl, eicosatrienyl, eicosatetraenyl, octadecinyl, nonadecinyl, eicosinyl and docosinyl, preferably from n-octanyl, n-nonanyl and 9Z-octadecenyl. 7. Use according to claim 5, characterized in that the compound has the general structure: wherein -R is selected from n-hexanyl, n-heptanyl, n-octanyl, n-nonanyl, n-decanyl. n-undecanyl, n-dodecanyl, n-tridecanyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, docosenyl, heptadecadienyl, octadecadienyl, nonadecadienyl, eicosadienyl, heptadecatrienyl, octadecatrienyl, nonadecatrienyl, eicosatrienyl, nonadecatetraenyl, heptadecinyl, octadecinyl, nonadecinyl and eicosinyl, preferably from n-heptanyl, n-octanyl and 8Z-heptadecenyl. 8. Use according to claim 7, characterized in that the compound is selected from N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide and N-((4-(2-methyl-2-aminopropoxy)-3 methoxyphenyl)-methyl)-nonanamide is selected. 9. Use according to any one of claims 1 to 8, characterized in that said compound is administered topically to the genital area to prevent the recurrence of lesions. 10. Use according to one of claims 1 to 9, characterized in that the compound is used for the treatment of herpes simplex type II infections.